Clinicopathological investigations in human amnesic patients and lesion studies in laboratory animals have provided convincing evidence that the hippocampal formation is essential for normal memory function. The hippocampus is a prominent target of neuropathology in the aged brain, and age-related memory deficits often mimic the effects of hippocampal damage. The specific neuropathological changes in the aged hippocampus that are responsible for senescent memory dysfunction, however, remain to be defined. The major objective of the proposed studies is to identify morphological alterations in the hippocampal formation and related structures that are associated with age-dependent memory impairment. It is becoming increasingly clear that memory impairment is not inevitable consequence of aging. Although many aged subjects are impaired in memory tasks that are dependent on the hippocampus, performance remains intact in other aged individuals. The proposed experiments will take advantage of this variability to identify those age-dependent neuroanatomical changes that are uniquely observed in brains from memory-impaired aged rates and monkeys. As a logical first step toward establishing a quantitative neuroanatomy of the aged hippocampal formation, the proposed program of studies will focus on the dentate gyrus; the simplest of the hippocampal fields. The total number and somal size of the principal cell type n the dentate gyrus, the granule cell, will be quantified using optical disector stereological method. The organization of dentate granule cell dendritic trees will be studied using intracellular Lucifer Yellow injection and quantitative three-dimensional computer reconstruction. Similar analyses will be conducted for layer II entorhinal cortical cells that provide the perforant path input to the dentate gyrus. Immunohistochemical methods will be used to visualize the cells of origin and terminal fields of: 1) the major cortical input to the dentate gyrus from layer II cells in the entorhinal cortex, 2) the major subcortical input to the dentate gyrus from the cholinergic cells of the septal complex, and 3) the prominent intrinsic complement of somatostatin-containing cells in the hilus of the dentate gyrus. For each chemically defined cell type, morphometric techniques will be used to determine whether the number and size of immunoreactive neurons is affected in the aged brain. Immunohistochemical material will be further evaluated using computer- assisted image analysis to define the effects of aging on the laminar organization and density of entorhinal, cholinergic, and somatostatinergic terminal fields in the molecular layer of the dentate gyrus. In each investigation, the principal aim will be to identify those neuroanatomical alterations that distinguish memory-impaired aged subjects from aged animals in which memory function remains intact. Taken together, these studies should yield significant insight into the neuropathological base of age-dependent cognitive dysfunction.